PHC 222 Part(I) Dr. Huda Al Salem Lecture (10)

How to improve water solubility? 1- Salt formation

1- Salt formation -Salt formation usually improves the water solubility of acidic and basic drugs as the salts of these drugs dissociate in water. -The degree of water solubility depends on the structure of the acid or base used to form the salt

1- Salt formation Example 1 Many GIT disturbances can be treated by ingestion of water-soluble compounds. Example 1 Tartaric acid >>>>Na K tartrate is used as mild laxative

1- Solubility - Salt formation is also used to change the taste of drugs to make them more palatable to the patient Example 2: Chlorpromazine HCl is water soluble but it has a very bitter taste. However, the water insoluble embonate salt is tasteless.. So it can be administered orally in the form of a suspension

How to improve water solubility? 2- Incorporation of water-solubilizing groups

2- Incorporation of water-solubilizing groups a- Type of group introduced b- Degree of permanency c- The biological effect of the group d- Methods of introduction

a- Type of group introduced 1- Incorporation of strongly polar alcohol, amine, amide, carboxylic acid, sulphonic acid and phosphorus oxyacid groups give analogues with water solubility higher than those formed by introduction of ether, aldehyde & ketonic functional groups. 2- Introduction of acidic and basic groups give a wide range for dosage forms that increase water solubility.

a- Type of group introduced 3- Zwitterions reduces water solubility. 4- Incorporation of weakly polar groups such as carboxylic acid esters, aryl halides & alkyl halides increases lipid solubility.

b- Degree of permanency 1- Groups that are bound directly to the carbon skeleton of the lead compound by C-C, C-O & C-N bonds are attached to by irreversible bonds. 2- Groups that are linked to the lead compound by ester, amide, phosphate & glycosidic links are more likely to be metabolized to reform the parent lead compound.

C- The position of the group In order to preserve the type of activity exhibited by the lead, the introduced group should be attached to a part of the structure that is not involved in the drug-receptor interaction (Pharmacophore).

C- The biological effect of the group Some groups have certain biological activity.. 1- acidic groups exhibit haemolytic properties. 2- aromatic acid groups exhibit anti-inflammatory activity 3- carboxylic acids with an alpha functional group exhibit chelation property. 4- Basic groups have a tendency to change the mode of action

d- Methods of introduction 1-Water-solubilising groups may be introduced at any stage in the synthesis of a drug. 2-Many methods involve the use of protecting groups. 3- Groups protected are either the water- solubilizing group or groups already present in the lead structure.

d- Methods of introduction e.g.: Acetal protection of a ketone during Reduction of an Ester.

d- Methods of introduction 1- COO- by acylation Chloramphenicol sodium succinate is supplied as a lyophilized powder which is dissolved only in water when needed & not more than 48 hours  

d- Methods of introduction 2- Sulphonic acid groups (-SO3H)

d- Methods of introduction 3- Basic groups -By alkylation or acylation -Amide derivatives are usually more stable than esters in aqueous solutions

d- Methods of introduction 4- Polyhydroxy groups

d- Methods of introduction 5- Ether groups

Solubility 3- Formulation Methods

Cosolvents Colloidal Solutions 3- Formulation Methods Cosolvents Colloidal Solutions

3- Formulation Methods A-Cosolvents a second solvent added to the original solvent, in small concentrations, to form a mixture that dissolve the solute. Requirements 1- Minimal toxic effect 2- Should not affect stability of the drug Example Paracetamol elixir in an aqueous solution is dissolved by the use of mixture of ethanol & 1,2-dihydroxypropane,

B-Colloidal Solutions 3- Formulation Methods B-Colloidal Solutions Prepared by dissolving a high concentration of the drug in an organic solvent that is miscible with water. Then, the concentrated solution is rapidly mixed with an aqueous solution containing a suitable stabilizer which adsorbed on the surface of the colloidal particles. Ex: Shaving Cream (Foam) (g in L) Mayonnaise (L in L) Blood (S in L)